scholarly journals The cell biology of polycystic kidney disease

2010 ◽  
Vol 191 (4) ◽  
pp. 701-710 ◽  
Author(s):  
Hannah C. Chapin ◽  
Michael J. Caplan
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Cell Biology ◽  
Fluid Transport ◽  
Genetic Disorder ◽  
Growth Control ◽  
Renal Tubules ◽  
Polycystic Kidney ◽  
Renal Epithelial Cell ◽  
Autosomal Dominant Polycystic Kidney

Polycystic kidney disease is a common genetic disorder in which fluid-filled cysts displace normal renal tubules. Here we focus on autosomal dominant polycystic kidney disease, which is attributable to mutations in the PKD1 and PKD2 genes and which is characterized by perturbations of renal epithelial cell growth control, fluid transport, and morphogenesis. The mechanisms that connect the underlying genetic defects to disease pathogenesis are poorly understood, but their exploration is shedding new light on interesting cell biological processes and suggesting novel therapeutic targets.

Pkd1-targeted mutation reveals a role for the Wolffian duct in autosomal dominant polycystic kidney disease

2019 ◽  
Vol 11 (1) ◽  
pp. 78-85 ◽  
Author(s):  
J. B. Tee ◽  
A. V. Dnyanmote ◽  
M. K. Lorenzo ◽  
O. R. Lee ◽  
S. Grisaru ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
High Throughput Sequencing ◽  
Autosomal Dominant ◽  
Cyst Formation ◽  
Wolffian Duct ◽  
Renal Tubules ◽  
Polycystic Kidney ◽  
Cystic Kidneys ◽  
Autosomal Dominant Polycystic Kidney

AbstractSeveral life-threatening diseases of the kidney have their origins in mutational events that occur during embryonic development. In this study, we investigate the role of the Wolffian duct (WD), the earliest embryonic epithelial progenitor of renal tubules, in the etiology of autosomal dominant polycystic kidney disease (ADPKD). ADPKD is associated with a germline mutation of one of the two Pkd1 alleles. For the disease to occur, a second event that disrupts the expression of the other inherited Pkd1 allele must occur. We postulated that this secondary event can occur in the pronephric WD. Using Cre-Lox recombination, mice with WD-specific deletion of one or both Pkd1 alleles were generated. Homozygous Pkd1-targeted deletion in WD-derived tissues resulted in mice with large cystic kidneys and serologic evidence of renal failure. In contrast, heterozygous deletion of Pkd1 in the WD led to kidneys that were phenotypically indistinguishable from control in the early postnatal period. High-throughput sequencing, however, revealed underlying gene and microRNA (miRNA) changes in these heterozygous mutant kidneys that suggest a strong predisposition toward developing ADPKD. Bioinformatic analysis of this data demonstrated an upregulation of several miRNAs that have been previously associated with PKD; pathway analysis further demonstrated that the differentially expressed genes in the heterozygous mutant kidneys were overrepresented in signaling pathways associated with maintenance and function of the renal tubular epithelium. These results suggest that the WD may be an early epithelial target for the genetic or molecular signals that can lead to cyst formation in ADPKD.

scholarly journals Examining the Role of HIPPO/YAP and AMOT Dysregulation and Imbalance in Autosomal Dominant Polycystic Kidney Disease

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
John Underwood ◽  
Robert L. Bacallao
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Autosomal Dominant ◽  
Genetic Disorder ◽  
Ectopic Expression ◽  
Renal Dialysis ◽  
National Institutes Of Health ◽  
Polycystic Kidney ◽  
Autosomal Dominant Polycystic Kidney

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a genetic disorder, most commonly caused by mutations in Polycystin-1 and Polycystin-2 (PC1 and PC2), in which many large lumenal cysts develop in the kidney epithelium. The disease is progressive and ultimately leads to renal dialysis and/or kidney transplant given the lack of efficacious therapeutic intervention. Current research has implicated HIPPO/YAP pathway dysregulation and AMOT imbalance following defects in cell-cell adhesion and contact inhibition as the molecular basis for ADPKD. To test this hypothesis as to the minimum cellular changes necessary to produce cystogenesis, the Bacallao lab microinjected normal human kidney epithelial (HK2) cells in order to drive ectopic expression of Cadherin-8 (CAD-8). Our Imaging with confocal microscopy and subsequent image analysis indicates CAD-8, a cadherin abnormally expressed in renal epithelial cells of ADPKD patients, is sufficient to cause formation of cysts albeit with uncharacteristically small lumens compared to typical ADPKD cysts. However, these cells exhibit significantly larger cyst expansion when they are transduced for coexpression of CAD-8 and constitutively active YAP5SA. Cells modified for heterozygosity with respect to a defective PC1 gene (PKD) also exhibited significantly larger lumen cysts when transduced with YAP5SA reinforcing the role of Yap in lumen size control. Finally, PKD cells transduced with AMOTL1 exhibited significantly smaller lumen sizes. AMOTL1 belongs to a family of adapter proteins which bind and inhibit Yap activity thus showing conclusively that positive and negative modulation of Yap activity correlates with cyst lumen size expansion and reduction respectively. “This project was funded, in part, with support from the O’Brien Center for Advanced Renal Microscopic Analysis funded, in part by P30 DK079312 from the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.”

scholarly journals Primary Aldosteronism in a Patient with Autosomal Dominant Polycystic Kidney Disease Associated with Polycystic Liver Disease

2018 ◽  
Vol 24 (1) ◽  
pp. 55-59
Author(s):  
Pană Camelia ◽  
Fâșie Dragoș ◽  
Voinea Claudia ◽  
Tuță Liliana Ana
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Autosomal Dominant ◽  
Genetic Disorder ◽  
Polycystic Kidney ◽  
Abdominal Ct ◽  
Polycystic Liver ◽  
Abdominal Ct Scan ◽  
Autosomal Dominant Polycystic Kidney ◽  
Low Activity

Abstract Polycystic kidney disease is an autosomal dominant genetic disorder (ADPKD) associated with arterial hypertension, as a common and early manifestation. However, the combination of hypertension and hypokalemia is very rare in these patients and may have another cause. We present a case of a 45 years old man with ADPKD associated with primary hyperaldosteronism. Unilateral suprarenal macroadenoma on abdominal CT scan, severe hypokalemia and low activity of plasmatic renin led to diagnosis.

scholarly journals KIM-1 and Kidney Disease Progression in Autosomal Dominant Polycystic Kidney Disease: HALT-PKD Results

2020 ◽  
Vol 51 (6) ◽  
pp. 473-479
Author(s):  
Benjamin R. Griffin ◽  
Zhiying You ◽  
Lama Noureddine ◽  
Berenice Gitomer ◽  
Loni Perrenoud ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Disease Progression ◽  
Polycystic Kidney Disease ◽  
Autosomal Dominant ◽  
Mixed Effects ◽  
Kidney Volume ◽  
Renal Tubules ◽  
Polycystic Kidney ◽  
Autosomal Dominant Polycystic Kidney ◽  
Over Time

Background: Cyst compression of renal tubules plays a role in the progression of autosomal dominant polycystic kidney disease (ADPKD) and may induce expression of kidney injury molecule-1 (KIM-1). Whether urinary KIM-1 indexed for creatinine (uKIM-1/Cr) is a prognostic marker of disease progression in ADPKD is unknown.In this secondary analysis of a prospective cohort study, we sought to determine whether patients with high as opposed to low uKIM-1/CR at baseline had greater rates of eGFR loss and height-adjusted total kidney volume (HtTKV) increase. Methods: Baseline uKIM-1/Cr values were obtained from 754 participants in Halt Progression of Polycystic Kidney Disease (HALT-PKD) studies A (early ADPKD) and B (late ADPKD). The predictor was uKIM-1/Cr, which was dichotomized by a median value of 0.2417 pg/g, and the primary outcomes were measured longitudinally over time. Mixed-effects linear models were used in the analysis to calculate the annual slope of change in eGFR and HtTKV. Results: Patients with high uKIM-1/Cr (above the median) had an annual decline in eGFR that was 0.47 mL/min greater than that in those with low uKIM-1/Cr (p = 0.0015) after adjustment for all considered covariates. This association was seen in study B patients alone (0.45 mL/min; p = 0.009), but not in study A patients alone (0.42 mL/min; p = 0.06). High baseline uKIM-1/Cr was associated with higher HtTKV in the baseline cross-sectional analysis compared to low uKIM-1/Cr (p = 0.02), but there was no difference between the groups in the mixed-effects model annual slopes. Conclusion: Elevated baseline uKIM-1/Cr is associated with a greater decline in eGFR over time. Further research is needed to determine whether uKIM-1/Cr improves risk stratification in patients with ADPKD.

scholarly journals Cyst Reduction by Melatonin in a Novel Drosophila Model of Polycystic Kidney Disease

Molecules ◽  
2020 ◽  
Vol 25 (22) ◽  
pp. 5477
Author(s):  
Cassandra Millet-Boureima ◽  
Roman Rozencwaig ◽  
Felix Polyak ◽  
Chiara Gamberi
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Malpighian Tubules ◽  
Cystic Degeneration ◽  
Renal Tubules ◽  
Potential Candidate ◽  
Polycystic Kidney ◽  
Melatonin Administration ◽  
Drosophila Model ◽  
Autosomal Dominant Polycystic Kidney

Autosomal dominant polycystic kidney disease (ADPKD) causes progressive cystic degeneration of the renal tubules, the nephrons, eventually severely compromising kidney function. ADPKD is incurable, with half of the patients eventually needing renal replacement. Treatments for ADPKD patients are limited and new effective therapeutics are needed. Melatonin, a central metabolic regulator conserved across all life kingdoms, exhibits oncostatic and oncoprotective activity and no detected toxicity. Here, we used the Bicaudal C (BicC) Drosophila model of polycystic kidney disease to test the cyst-reducing potential of melatonin. Significant cyst reduction was found in the renal (Malpighian) tubules upon melatonin administration and suggest mechanistic sophistication. Similar to vertebrate PKD, the BicC fly PKD model responds to the antiproliferative drugs rapamycin and mimics of the second mitochondria-derived activator of caspases (Smac). Melatonin appears to be a new cyst-reducing molecule with attractive properties as a potential candidate for PKD treatment.

scholarly journals Cyst Reduction in a Polycystic Kidney Disease Drosophila Model Using Smac Mimics

Biomedicines ◽  
2019 ◽  
Vol 7 (4) ◽  
pp. 82 ◽  
Author(s):  
Cassandra Millet-Boureima ◽  
Ramesh Chingle ◽  
William D. Lubell ◽  
Chiara Gamberi
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Critical Evaluation ◽  
Substantial Reduction ◽  
Surrounding Tissue ◽  
Renal Tubules ◽  
Polycystic Kidney ◽  
Precise Knowledge ◽  
Drosophila Model ◽  
Autosomal Dominant Polycystic Kidney

Autosomal dominant polycystic kidney disease (ADPKD) is an inherited malady affecting 12.5 million people worldwide. Therapeutic options to treat PKD are limited, due in part to lack of precise knowledge of underlying pathological mechanisms. Mimics of the second mitochondria-derived activator of caspases (Smac) have exhibited activity as antineoplastic agents and reported recently to ameliorate cysts in a murine ADPKD model, possibly by differentially targeting cystic cells and sparing the surrounding tissue. A first-in-kind Drosophila PKD model has now been employed to probe further the activity of novel Smac mimics. Substantial reduction of cystic defects was observed in the Malpighian (renal) tubules of treated flies, underscoring mechanistic conservation of the cystic pathways and potential for efficient testing of drug prototypes in this PKD model. Moreover, the observed differential rescue of the anterior and posterior tubules overall, and within their physiologically diverse intermediate and terminal regions implied a nuanced response in distinct tubular regions contingent upon the structure of the Smac mimic. Knowledge gained from studying Smac mimics reveals the capacity for the Drosophila model to precisely probe PKD pharmacology highlighting the value for such critical evaluation of factors implicated in renal function and pathology.

scholarly journals Autosomal dominant polycystic kidney disease: recent advances in clinical management

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 2029 ◽  
Author(s):  
Zhiguo Mao ◽  
Jiehan Chong ◽  
Albert C. M. Ong
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Clinical Management ◽  
Cell Biology ◽  
Patient Management ◽  
Autosomal Dominant ◽  
Clinical Medicine ◽  
Polycystic Kidney ◽  
Major Genes ◽  
Autosomal Dominant Polycystic Kidney

The first clinical descriptions of autosomal dominant polycystic kidney disease (ADPKD) go back at least 500 years to the late 16th century. Advances in understanding disease presentation and pathophysiology have mirrored the progress of clinical medicine in anatomy, pathology, physiology, cell biology, and genetics. The identification of PKD1 and PKD2, the major genes mutated in ADPKD, has stimulated major advances, which in turn have led to the first approved drug for this disorder and a fresh reassessment of patient management in the 21st century. In this commentary, we consider how clinical management is likely to change in the coming decade.

Too close not to encyst: Polycystic kidney disease and interorganellar contact sites

2019 ◽  
Vol 12 (583) ◽  
pp. eaaw6996
Author(s):  
Isotta Lorenzi ◽  
Luca Scorrano
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Genetic Disorder ◽  
Polycystic Kidney ◽  
Mitofusin 2 ◽  
Contact Sites ◽  
Autosomal Dominant Polycystic Kidney ◽  
Common Genetic Disorder

Mitofusin 2 (MFN2) tethers mitochondria to the endoplasmic reticulum (ER). In the 7 May 2019 issue of Science Signaling, Kuo et al. report that polycystin 2 (PC2), encoded by a gene mutated in type 2 autosomal dominant polycystic kidney disease (ADPKD), contributes to cystogenesis by affecting MFN2, thus extending the role of mitochondria-ER contact sites to a common genetic disorder.

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